Flexible neural probes

ABSTRACT

Embodiments include microelectrodes including a flexible shank and a bioabsorbable material surrounding the flexible shank. The flexible shank can include a flexible substrate, a circuit, and a plurality of sensors. Embodiments also include a methods of forming flexible active electrode arrays including depositing a flexible polymer on a substrate. The methods also include forming a plurality of sensors on the flexible polymer and attaching a silicon-based chip to the flexible shank. The methods also include coating the flexible shank in a bioabsorbable material and cutting the shank and a portion of the bioabsorbable material from the substrate.

DOMESTIC PRIORITY

This application is a divisional of and claims priority from U.S. patentapplication Ser. No. 15/268,020, filed on Sep. 16, 2016, entitled“FLEXIBLE NEURAL PROBES”, the entire contents of which are incorporatedherein by reference.

BACKGROUND

The present invention relates generally to electrodes for studyingneural activity, and more specifically to flexible activemicroelectrodes for studying neural activity.

Microelectrodes can be useful in recording and analyzing neuronalactivity in brain tissue. Microelectrode arrays can contain multipleshanks that form an interface between neurons and electronic devices.Microelectrodes for use in such applications can be active or passive.Passive electrodes can include wiring and electronic probes, wherein thenumber of sensors is limited by wiring. Active electrodes includeelectrodes that have built in circuitry, and they can have greaterdensity than passive electrodes.

SUMMARY

In accordance with one or more embodiments, a microelectrode includes aflexible shank. The flexible shank includes a flexible substrate. Theflexible shank also includes a circuit. The flexible shank also includesa plurality of sensors. The microelectrode also includes a bioabsorbablematerial surrounding the flexible shank.

In accordance with another embodiment, a method of measuring neuralactivity includes embedding a flexible active electrode shank includinga plurality of sensors in a bioabsorbable material. The method alsoincludes implanting the flexible active electrode shank in a biologicaltissue. The method also includes sensing neural activity with thesensors.

In accordance with a further embodiment, a method of forming a flexibleactive electrode array includes depositing a flexible polymer on asubstrate. The method also includes forming a plurality of sensors onthe flexible polymer to create a flexible shank. The method alsoincludes attaching a silicon-based chip to the flexible shank. Themethod also includes coating the flexible shank and the silicon-basedchip in a bioabsorbable material. The method also includes cutting theflexible shank and the silicon-based chip and a portion of thebioabsorbable material from the substrate.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter of embodiments of the invention is particularlypointed out and distinctly claimed in the claims at the conclusion ofthe specification. The foregoing and other features and advantages ofthe one or more embodiments described herein are apparent from thefollowing detailed description taken in conjunction with theaccompanying drawings in which:

FIG. 1 illustrates an exemplary flexible active electrode shankaccording to one or more embodiments.

FIG. 2 illustrates an exemplary flexible active electrode shank embeddedin bioabsorbable material according to one or more embodiments.

FIG. 3 illustrates an exemplary flexible active electrode arrayaccording to one or more embodiments.

FIGS. 4-7 illustrate an exemplary method of forming a flexible activeelectrode array including a bioabsorbable material according to one ormore embodiments, in which:

FIG. 4A illustrates a top-down view of exemplary active flexibleelectrode arrays after forming the arrays on a substrate;

FIG. 4B illustrates a cross-sectional side view of the exemplaryelectrode arrays formed on a substrate illustrated in FIG. 4A;

FIG. 5 illustrates a top-down view of exemplary electrode arrays afterembedding the arrays in bioabsorbable material according to one or moreembodiments;

FIG. 6 illustrates an exemplary electrode array after removing an arrayembedded in bioabsorbable material from the substrate;

FIG. 7 illustrates an exemplary electrode array after a portion of thebioabsorbable material is removed from the array.

FIG. 8 illustrates an exemplary transistor on a flexible substrateaccording to one or more embodiments.

FIG. 9 is a flow diagram illustrating an exemplary method of measuringneural activity according to one or more embodiments.

FIG. 10 is a flow diagram illustrating an exemplary method of forming aflexible active electrode array according to one or more embodiments.

DETAILED DESCRIPTION

Embodiments of the invention relate to flexible active neuralmicroelectrodes and related methods of manufacture. The use of activeelectrodes in the study of neural activity is desirable. However, thesensitive tissues of the brain can be highly susceptible to damage uponinsertion of a rigid material, such as those commonly used for activeelectrodes.

Passive electrodes can be used in the study of neural activity byinsertion into the brain. Passive electrodes can include a number ofsensors connected to flexible wires. Such electrodes can be sufficientlyflexible to minimize damage to brain tissue, for example, upon movementof a patient due to respirator or cardiac cycles. However, the number ofsensors can be limited by wiring as each probe can be associated with awire.

Active electrodes can provide greater functionality in neurologicalapplications, for instance, by multiplexing and amplifying theelectrical current. However, conventional shanks for active electrodesinclude a rigid material, such as silicon, which can damage theneighboring tissue and have poor contact and, thus, reduced stabilitydue to the lack of movement of the shank during respiratory or cardiaccycles.

Active electrodes can have improved density in comparison with passiveelectrodes and can have built in circuitry, making them desirable for anumber of applications, including the study of neural activity. Howeverconventional active electrode materials, for instance a TiN (titaniumnitride) electrode with built in circuitry, are rigid resulting indamage to surrounding brain tissue. This rigidity can make suchelectrodes unsuitable for long-term studies and undesirable for shortterm studies.

The active electrodes described herein are be suitable for both shortterm and long term studies of neural activity. Flexible activeelectrodes can improve compliance between electrode and tissue and canminimize tissue damage. In one or more embodiments, flexible activeelectrodes are manufactured on a substrate, and then made suitably rigidfor insertion into neural tissue by coating with a bio-dissolvablematerial. After dissolution of the rigid material upon insertion intothe neural tissue, flexible active electrodes become sufficientlyflexible to be suitable for short and long term studies of neuralactivity. Moreover, flexible active electrodes, according to one or moreembodiments, have increased functionality or sensitivity in comparisonwith passive electrodes.

FIG. 1 illustrates an exemplary flexible active electrode shank 100according to one or more embodiments. As is shown, the flexible activeelectrode shank 100 can include a flexible substrate 102. Within theflexible substrate 102 can be one or more circuits 104. The circuits canbe connected to one another or to external components by a plurality ofcircuit wires 110. In some embodiments, each of the plurality ofcircuits 104 can be attached to another circuit 104 or to one or moresensor pixels 106 by way of a sensor wire 112. Sensor wires 112 andcircuit wires 110 can be any conductive wire used in microelectronicsand can be composed of the same materials or different materials. Thesensor pixels 106 can contain a sensor or electrode 108.

Flexible substrate 102 can include a flexible polymeric material. Forinstance, the flexible substrate 102 can include, in some embodiments,polydimethylsiloxane (PDMS), polyimide (PI), polyurethane (PU),polymethylmethacrylate (PMMA), polyethylene terephthalate (PET),polystyrene, polycarbonate, polyvinyl alcohol (PVA), polybenzimidazole,polyester, and combinations thereof.

Circuits 104 can include any circuitry useful for detecting andprocessing neural activity. For example, and not by way of limitation,circuits 104 can include multiplexers (MUX) or demultiplexers (deMUX),signal conditioning circuits such as amplifiers and filters made byflexible electronics. For instance, in some embodiments, circuits caninclude metals, carbon nanotubes, graphene nanoribbons, or other relatedmaterials.

Sensor pixel 106 can include, in some embodiments, flexiblecomplementary metal-oxide-semiconductor (CMOS) circuitry and can house asensor or electrode 108. The CMOS circuits can include, for example,n-type field effect transistors (n-FETs) and p-type field effecttransistors (p-FETs) fabricated with carbon nanotubes as channelmaterials. The sensor 108 or electrode can be any flexible sensor orelectrode useful for studies of neural activity. Sensors 108 caninclude, for instance, metal, carbon nanotubes, graphene, or relatedmaterials.

As is illustrated in FIG. 2, in some embodiments, the flexible shank 100can be embedded in a bioabsorbable material 120. Bioabsorbable material120 can by any material is sufficiently rigid to withstand stressaccompanying implantation of the flexible shank, that can be safelyadministered to biological tissue and that can be absorbed, degraded, orsoftened by adjacent biological tissue. Exemplary bioabsorbablematerials include, but are not limited to gelatin, polyglycolic acids(PGA), such as crystalline PGAs, and polylactic acids (PLA), includingfor instance poly-L-lactic acid (PLLA), poly-D-lactic acid, andamorphous PLA. In some embodiments, the bioabsorbable material 120 candissolve after implantation, leaving a highly flexible active electrode.In some embodiments, the highly flexible active electrode can have highsensor density.

In some embodiments, a flexible shank can be part of an array. FIG. 3illustrates an exemplary array of flexible active electrodes 200. Thearray 200 includes a plurality of electrode shanks 202, each shankhaving a top end 203 and a bottom end 205. The shanks 202 include aflexible polymer substrate 210 and a plurality of circuits, includingrouting circuits 206 and sensor circuits 208. Polymer substrate 210includes a material such as those described for flexible substrate 102.In some embodiments, for instance, polymer substrate 210 includes PDMSor PI. In some embodiments, the polymer substrate 210 has a length ofgreater than or equal to 5 millimeters (mm) from the top end to thebottom end, such as from 5 mm to 10 mm. The polymer substrate 210 has awidth, in some embodiments, of 50 to 75 micrometers (μm).

The routing circuits 206 include, in some embodiments, flexiblecircuits, such as flexible carbon nanotube circuits. The routingcircuits 206 also include, in some embodiments, routing elements.

The sensor circuits 208 include, in some embodiments, flexible circuits,such as flexible carbon nanotube circuits. The sensor circuits 208 alsoinclude, in some embodiments, sensors. In some embodiments, the sensorsinclude CMOS sensors having electrically isolated active regions.Preferably, a sensor circuit 208 is capable of receiving signals fromand/or applying signals to neurons in one or more embodiments. In someembodiments, the sensor circuits 208 include a pH sensor. In someembodiments, the sensor circuits 208 include an action potential sensor.In some embodiments, the sensor circuits 208 include a local fieldpotential (LFP) sensor. In some embodiments, the number of sensorcircuits per shank is 10 to 50. In preferred embodiments, the number ofsensor circuits per shank is 20 to 40, or 25 to 35, or 30 to 35.

In some embodiments, the array 200 includes an end chip 204, such as aCMOS end chip. The end chip 204 can be adjacent or near the top end 203of the flexible shank. In some embodiments, every electrode shank 202contains an end chip 204. In some embodiments, the end chip 204 is incommunication with the sensor circuits 208 or routing circuits 206. Insome embodiments, the end chip 204 is in communication with an externaldevice (not shown).

In some embodiments, a flexible shank or an array is embedded in abioabsorbable material, such as gelatin, for implantation intobiological tissue. For example, the bioabsorbable material can impartsufficient rigidity to the flexible electrodes such that they can beinserted into the biological tissue. After insertion, the bioabsorbablematerial can lose its rigidity, by dissolution, absorption, or by othermeans, to minimize damage to the biological tissue during the course ofstudy or investigation.

FIGS. 4 to 7 illustrate an exemplary method of forming a flexible activeelectrode array including a bioabsorbable material according to one ormore embodiments. FIG. 4A illustrates a top-down view of exemplaryactive flexible electrode arrays 200 after forming the arrays 200 on asubstrate 222. FIG. 4B illustrates a cross-sectional side view of theexemplary electrode arrays formed on a substrate illustrated in FIG. 4A.The substrate 222 can include, for example, a semiconductor material 226and a sacrificial polymer layer 224. The semiconductor material 226 canbe made of, for example, silicon (e.g., such as a silicon wafer),silicon germanium, or other suitable rigid supporting material. Thesacrificial polymer layer 224 is used to release final fabricatedflexible shanks from the supporting substrate 226. A flexible substrate102 can be deposited on the substrate 222. Sensors and chips, such asCMOS end chips, and wiring of the arrays 200, as described above, can befabricated according to known processes.

As is illustrated in FIG. 5, the active flexible electrode arrays 200can be embedded in a bioabsorbable material 120 by coating the wafer 220in a bioabsorbable material 120, such as gelatin.

As is illustrated in FIG. 6, after coating the wafer 220 in abioabsorbable material 120, an array 200 and adjacent bioabsorbablematerial 120 can be removed from the wafer. For example, in someembodiments, an array 200 is cut from the supporting wafer with lasermilling. The bioabsorbable material 120 can surround the polymersubstrate 210 and circuits 206, 208. In some embodiments, thebioabsorbable material 120 surrounds the end chips 204. In someembodiments, the bioabsorbable material 120 has a thickness of 15 to 20μm and a width of 75 to 100 μm.

In some embodiments, an array and adjacent bioabsorbable material cutfrom the supporting wafer are inserted or implanted into biologicaltissue. After implanting an array into biological tissue, bioabsorbablematerial 120 can be removed from the polymer substrate 210 and sensors206, 208, leaving active flexible electrode shanks 230, as are depictedin FIG. 7. In some embodiments, the bioabsorbable material is removed byabsorption into surrounding biological tissue.

FIG. 8 illustrates an exemplary transistor 300 on a flexible substrate.As is shown, the transistor 300 can include a flexible substrate 102.The transistor 300 includes a work function metal in some embodiments.In some embodiments, the transistor 300 includes a low resistance metal.

In some embodiments, a first gate metal 301 can be deposited on theflexible substrate 102. First gate metal 301 can include, for example, aconductive metal such as gold.

In some embodiments, a second gate metal 302 can be deposited on thefirst gate metal 301. Second gate metal 302 can include a conductivemetal such as titanium.

A gate dielectric 304 can be deposited on the second gate metal 302. Insome embodiments, a layer of aminopropyltriethoxysilane (APTES) 306 anda carbon nanotube (CNT) layer 308, such as a CNT monolayer, can bedeposited on the gate dielectric 304.

Electrodes 310 can be patterned on the transistor 300 and can include asource and drain region. In some embodiments, the source and drain canbe high work-function material (e.g., palladium) for forming a p-typetransistor. In some embodiments, the source and drain can be lowwork-function material (e.g., scandium) for forming an n-typetransistor. Gate dielectric 304 can include, for example, a high-κ gatedielectric. Gate dielectric 304 includes, in some embodiments, an oxidematerial, such as aluminum oxide.

Referring now to FIG. 9, a flow diagram of a method 400 for measuringneural activity in accordance with an exemplary embodiment is shown. Asshown at block 402, the method 400 includes embedding a flexible activeelectrode shank including sensors in a bioabsorbable material. Next asshown at block 404, the method includes implanting flexible activeelectrode shanks in biological tissue. In some embodiments, the method400 also includes, as shown at block 406, dissolving the bioabsorbablematerial in the biological tissue. Next, as shown at block 408, themethod 400 includes sensing neural activity with the sensors.

In some embodiments, the method 400 also includes routing a signalreceived by the sensors, such as a neural signal (not shown). In someembodiments, the method 400 includes amplifying a signal received by thesensors (not shown). In some embodiments, the method 400 can includeproviding an output to the biological tissue, such as providing a signalto neural tissue (not shown).

Sensors can include electronic components capable of receiving a signalfrom biological tissue. Exemplary signals from biological tissue caninclude, but are not limited to, action potential, pH, or local fieldpotential. Sensors can also include, in some embodiments, electroniccomponents capable of providing an output to biological tissue or toother electronic components. In some embodiments, for example, sensorscan include electrodes that provide an electrical signal to adjacentbiological tissue.

Referring now to FIG. 10, a flow diagram of a method 500 for forming aflexible active electrode array in accordance with an exemplaryembodiment is shown. As shown at block 502, the method 500 includesdepositing a flexible polymer on a substrate. Next as shown at block504, the method includes forming sensors on the flexible polymer tocreate a flexible shank. In some embodiments, the method 500 alsoincludes, as shown at block 506, attaching a silicon-based chip to theflexible shank. Next, as shown at block 508, the method 500 includescoating the flexible shank and silicon-based chip in a bioabsorbablematerial. The method 500 also includes, as shown at block 510, cuttingthe flexible shank and silicon-based chip and a portion of thebioabsorbable material from the substrate.

In some embodiments, method 500 also includes laser milling the flexibleshank, silicon-based chip, and a portion of the bioabsorbable materialfrom the substrate (not shown).

In some embodiments, method 500 includes forming an array of flexibleshanks and coating the array of flexible shanks in the bioabsorbablematerial (not shown). In some embodiments, method 500 includes cuttingthe array and a portion of the bioabsorbable material from thesubstrate, for example by laser milling (not shown).

Deposition is any process that grows, coats, or otherwise transfers amaterial onto the wafer. Available technologies include, but are notlimited to, thermal oxidation, physical vapor deposition (PVD), chemicalvapor deposition (CVD), electrochemical deposition (ECD), molecular beamepitaxy (MBE) and more recently, atomic layer deposition (ALD) amongothers.

Removal is any process that removes material from the wafer: examplesinclude etch processes (either wet or dry), chemical-mechanicalplanarization (CMP), laser milling, etc.

Patterning is the shaping or altering of deposited materials, and isgenerally referred to as lithography. For example, in conventionallithography, the wafer is coated with a chemical called a photoresist;then, a machine called a stepper focuses, aligns, and moves a mask,exposing select portions of the wafer below to short wavelength light;the exposed regions are washed away by a developer solution. Afteretching or other processing, the remaining photoresist is removed.Patterning also includes electron-beam lithography, nanoimprintlithography, and reactive ion etching.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, integers, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, integers, steps, operations, element components,and/or groups thereof.

The corresponding structures, materials, acts, and equivalents of allmeans or step plus function elements in the claims below are intended toinclude any structure, material, or act for performing the function incombination with other claimed elements as specifically claimed. Thedescription of the present invention has been presented for purposes ofillustration and description, but is not intended to be exhaustive orlimited to the invention in the form described. Many modifications andvariations will be apparent to those of ordinary skill in the artwithout departing from the scope and spirit of the invention. Theembodiment was chosen and described in order to best explain theprinciples of the invention and the practical application, and to enableothers of ordinary skill in the art to understand the invention forvarious embodiments with various modifications as are suited to theparticular use contemplated.

The flow diagrams depicted herein are just one example. There can bemany variations to this diagram or the steps (or operations) describedtherein without departing from the spirit of embodiments of theinvention. For instance, the steps can be performed in a differing orderor steps can be added, deleted or modified. All of these variations areconsidered a part of the claimed invention.

The descriptions of the various embodiments of the present inventionhave been presented for purposes of illustration, but are not intendedto be exhaustive or limited to the embodiments described. Manymodifications and variations will be apparent to those of ordinary skillin the art without departing from the scope and spirit of the describedembodiments. The terminology used herein was chosen to best explain theprinciples of the embodiments, the practical application or technicalimprovement over technologies found in the marketplace, or to enableothers of ordinary skill in the art to understand the embodimentsdescribed herein.

What is claimed is:
 1. A method of measuring neural activity, the methodcomprising: providing a flexible substrate comprising a polymericmaterial over a rigid semiconductor substrate; providing a plurality ofactive electrodes on the flexible substrate to define a flexible activeelectrode shank, each active electrode comprising a gate directly on asurface of the polymeric material, a gate dielectric over the gate, anaminopropyltriethoxysilane (APTES) layer on a surface of the gatedielectric and the surface of the polymeric material, and a carbonnanotube monolayer on a surface of the APTES layer; embedding theflexible active electrode shank in a bioabsorbable material; releasingthe flexible active electrode shank from the rigid semiconductorsubstrate; implanting the flexible active electrode shank in abiological tissue; dissolving the bioabsorbable material in thebiological tissue; and sensing neural activity using the plurality ofactive electrodes.
 2. The method of claim 1 further comprising routing aneural signal.
 3. The method of claim 1 further comprising detecting apH local to the flexible active electrode shank.
 4. The method of claim1 further comprising detecting action potential.
 5. The method of claim1 further comprising detecting local field potential.
 6. The method ofclaim 1 further comprising amplifying a neural signal received from oneof the plurality of active electrodes.
 7. The method of claim 1 furthercomprising providing an output to the biological tissue.
 8. The methodof claim 7, comprising providing the output to a neural tissue.
 9. Themethod of claim 1, wherein the flexible active electrode shank furthercomprises a circuit embedded within the flexible substrate.
 10. Themethod of claim 9, wherein the circuit comprises a complimentarymetal-oxide semiconductor chip.
 11. The method of claim 1, wherein thebioabsorbable material comprises gelatin.
 12. The method of claim 1,wherein the plurality of active electrodes comprises a routing sensor.13. The method of claim 1, wherein the plurality of sensors comprises anaction potential sensor.
 14. The method of claim 1, wherein theplurality of active electrodes comprises greater than or equal to 25sensors.
 15. The method of claim 14, wherein the plurality of activeelectrodes comprises greater than or equal to 30 sensors.
 16. The methodof claim 1, wherein the flexible active electrode shank comprises amultiplexer.
 17. The method of claim 1, wherein the flexible activeelectrode shank comprises a demultiplexer.